This invention relates to the prevention and/or treatment of a condition or disease state in an individual which results from an excessive immune response.
Parasites are living entities that dwell on or in other creatures during some part of their life cycles, drawing nourishment from the host. Parasites that inhabit the intestines have a complex interplay with the mucosal immune system. They must establish a tranquil relationship with host mucosal defenses to survive.
Helminths are elaborate multicellular worms with complex life cycles and development. The nematodes (non-segmented roundworms) and the platyhelminths (flatworms) are the two groups of helminths that colonize the human intestines. Perhaps more than a third of the population of the world currently shelter one or more of these organisms. The lifetime exposure rate, however, is actually much more. The prevalence of helminths is highest in warm climates and in populations subject to crowding, poor sanitation and impure food supply. Inflammatory bowel disease (IBD), rheumatoid arthritis and autoimmune diseases are rare in these same regions.
Nematodes that frequently inhabit the human gut are Ascaris lumbricoides, Enterobius vermicularis (pin worm), Trichuris trichiura (whipworm), Ancylostoma duodenale and Necator americanus (hookworms), and Strongyloides stercoralis. Trichinella spiralis infests the small intestine briefly.
The platyhelminths include the trematodes and cestodes. The most common adult trematodes that reside in the human intestines are Fasciolopsis, Echinostoma and Heterophyes species. Those that live in the biliary system include Clonorchis sinensis, Opisthorchis viverrini and felineus, and Fasciola hepatica. Schistosoma dwell in the venous system, but several species chronically affect the gut by the passage of eggs through the intestinal wall. Adult cestodes commonly infecting humans are Diphyllobothrium species (fish tapeworm), Taenia saginata (beef tapeworm), Taenia solium (pork tapeworm) and Hymenolepsis nana (dwarf tapeworm).
The host acquires various helminthic species through contact with soil, food or water contaminated with the infective form of the parasite. Children most frequently harbor helminthic infections because of their close contact with soil and suboptimal hygienic practices. Helminths incite an intestinal Th2 response, which can cause worm expulsion or limit the magnitude of infection. Most children living in non-industrialized countries have these parasites. Many helminthic species survive for years within the gut, biliary tree or mesenteric veins making thousands of eggs daily. Thus, beginning in childhood, these worms and/or their ova release molecules that bathe the intestinal mucosal surface for years inciting Th2-type inflammation. Dysregulation of the immune system leading to an excessive Th1 response may be the cause of several human diseases. Some diseases due to dominant Th1 responses include IBD, rheumatoid arthritis, sarcoidosis, multiple sclerosis, and insulin-dependent diabetes melitis.
IBD is more common in temperate climates. It is not known what causes the geographic differences. Observations suggest an environmental exposure unique to temperate countries and highly industrialized societies predisposes to the development of IBD. An alternative explanation is that it is unhealthy to be raised in an xe2x80x9cover cleanxe2x80x9d environment. It is proposed herein that the major environmental factor predisposing to IBD is underexposure during childhood to intestinal helminths, which promote strong Th2-type inflammation.
The frequency of CD has increased substantially over the last 40 years. It is most prevalent in temperate regions that are highly industrialized. This suggests that there is some critical environmental factor responsible for the change in frequency. Also, ulcerative colitis is rare in underdeveloped countries. It is proposed according to the invention that the absence of exposure to intestinal helminthic infections in childhood is an important environmental factor favoring the development of CD and perhaps ulcerative colitis (UC).
People in industrialized countries are living in increasingly hygienic environments and are acquiring helminths much less frequently. The decreasing frequency of helminthic infections appears to correlated with the increasing prevalence of CD. A case in point is the marked increase in the frequency of CD in young Asians and Africans after residing in Israel for greater than 10 years. Also, the frequency of helminthic infestation differs between the Jewish Israelis and Arabs. In 1969, stool examinations of hospitalized patients in Arab-predominant East Jerusalem contained helminthic ova over 60% of the time. The frequency in Israeli-predominant East Jerusalem was 10% or less.
Thus, It is possible that the failure to acquire helminths and to experience mucosal Th2 conditioning predisposes to CD and UC. There is a need to combat CD and UC by re-colonization of the gastrointestinal tract with these organisms which may afford protection.
One object of the invention is to prevent or treat an excessive immune response in an individual. The excessive or aberrant immune response can be caused by an autoimmune disease, for example, IBD, rheumatoid arthritis, type 1 diabetes melitis, lupus erythematosis, sarcoidosis and multiple sclerosis.
Further, it is an object of the instant invention to provide a method of vaccinating an individual against autoimmune disease, for example, IBD, rheumatoid arthritis, type 1 diabetes melitis, lupus erythematosis, sarcoidosis and multiple sclerosis.
It is an object of the present invention to provide a method of creating an immune environment in an individual that is conducive to ameliorating IBD.
It is an object of the present invention to provide a pharmaceutical composition comprising a helminthic parasite and a pharmaceutically acceptable carrier.
It is a further object of the present invention to provide a pathogen-free helminthic parasite and an acceptable pharmaceutical carrier.
It is another object of the present invention to provide a method of preparing pathogen-free helminthic parasites.
The instant invention presents a method of preventing or treating an excessive immune response in an individual by administering an effective amount of an helminthic parasite preparation to reduce the excessive immune response in the individual.
The invention encompasses a method of treating an excessive immune response, including an aberrant/enhanced Th1 response, comprising administering a helminthic parasite preparation in an amount sufficient to reduce the excessive immune response.
As used herein, the term xe2x80x9chelminth parasite preparationxe2x80x9d refers to any one of a whole parasite, a parasite extract, parasite eggs, parasite egg extract, parasite larvae, parasite larvae extract, parasite cercariae and parasite cercariae extract.
The helminthic preparation may be selected from the group consisting of helminiths that naturally colonize humans and helminths that colonize animals but may protect humans from an excessive Th1 response.
In other preferred embodiments of the invention, the helminth parasite is a nematode, and may be selected from the group such as Ascaris lumbricoides, Enterobius vermicularis, Trichuris trichiura, Ancylostoma duodenale and Necator americanus, Strongyloides stercoralis and Trichinella spiralis. 
In other preferred embodiments of the invention, the helminthic parasite is a platyhelminth, and may be selected from the group consisting of trematodes and cestodes, such as Fasciolopsis, Echinostoma and Heterophyes species, Clonorchis sinensis, Opisthorchis viverrini, Opisthorchis felineus, Fasciola hepatica, Schistosoma species, Diphyllobothrium species, Taenia saginata, Taenia solium and Hymenolepsis nana. 
In other preferred embodiments, the helminthic parasite is selected from the group consisting of filarial parasites and lung flukes.
In additional embodiments, the helminthic parasites are selected from the group consisting of Trichuris muris, Trichinella spiralis, Nippostrongylus prasiliensis, Heligmonsomoides polygyrus, Hymenolepsis nanan, Angiostrongylus species, Trichuris suis, Ascaris suum, Trichuris vulpis, Toxocara species, Gnathostoma species, Ancylostoma species, Anisakis species and Pseudoterranova species.
The invention also encompasses a method of preventing or treating an autoimmune disease in an individual comprising administering a helminthic parasite in an amount sufficient to prevent or treat the autoimmune disease in an individual.
As used herein, the term xe2x80x9cautoimmune diseasexe2x80x9d refers to diseases such as IBD, rheumatoid arthritis, type 1 diabetes mellitus, lupus erythematosus, sarcoidosis and multiple sclerosis
The xe2x80x9ceffective dosagexe2x80x9d amount of the helminthic parasite preparation is dependent upon the specific cause for the excessive or aberrant immune response, and is addressed in detail below.
As used herein, the term xe2x80x9cexcessivexe2x80x9d or xe2x80x9caberrantxe2x80x9d immune response refers to a T helper cell type 1 (Th1) response in which the activity of T helper 1 cells is elevated in an individual relative to the activity of such cells in an individual who is not affected by the disease. Typically, the elevation of the Th1 response in the diseased individual will be at least 2-fold, and possible 5-fold-10-fold above the Th1 response in an individual who is not diseased. Th1-type inflammations produce large amounts of IFN-xcex3 and TNFxcex1, which in turn stimulate a strong cellular immune reaction. These are some of the cytokines that may be measured to indicate an excessive or aberrant Th1 response, as described in detail hereinbelow.
Preferably, the helminthic parasite is selected from the group consisting of parasite, parasite extract, parasite eggs, parasite egg extract, parasite larvae, parasite larvae extract, cercariae and cercariae extract.
The invention also encompasses a method of treating IBD comprising administering a helminthic parasite preparation in an amount sufficient to reduce IBD.
The invention also encompasses a method of vaccinating an individual against a disease involving an excessive immune response comprising administering a helminthic parasite preparation in an amount sufficient to prevent the excessive immune response.
The invention also encompasses a pharmaceutical composition comprising a helminthic parasite preparation, and a pharmaceutically acceptable carrier.
Further features and advantages of the invention will become more fully apparent in the following description of the embodiments and drawings thereof, and from the claims.